Stroke is the third leading cause of death and leading cause of adult disability in the United States. To date, intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is the only treatment proven to be effective for patients with ischemic stroke. Despite its proven efficacy, the use of rt- PA for stroke treatment has been limited. While many factors may contribute to the reluctance to use rt-PA for stroke treatment, one potentially major limitation of rt-PA is the 6.4% rate of symptomatic intracranial hemorrhage associated with its use. A safer agent with a reduced rate of hemorrhage and with improved efficacy might enjoy more widespread use, with resulting further reductions in patient morbidity and costs of care. Tenecteplase (TNK) is a modified rt-PA with a longer half-life, greater fibrin specificity, and increased resistance to plasminogen activator inhibitor - I (PAI-I) that has been approved for use in patients with acute myocardial infarction (MI). In MI patients, TNK is associated with less systemic bleeding than rt PA, and in an animal model of schemic stroke, it may be associated with less intracranial bleeding than rt PA. In June, 2000, the applicants began a National Institutes of Health-funded pilot dose escalation safety study of TNK in patients with acute ischemic stroke. Beginning with an initial dose chosen to be bioequivalent to the approved dose ofrt-PA for stroke, 3 sequential escalating doses of TNK were tested between 0.1 mg/kg and 0.4 mg/kg without any symptomatic intracranial hemorrhages being observed. Three month outcome data suggest that there may be a corresponding reduction in severe disability and death associated with TNK treatment. These promising results warrant further testing of TNK in acute ischemic stroke. The proposal outlined herein describes a large, multi-center, randomized controlled clinical trial comparing TNK to rt-PA in patients with acute ischemic stroke treated within 3 hours of onset. Embedded within the overall trial is a smaller, Phase 2B trial that will a) select the proper dose of TNK to carry forward for further study; b) provide further evidence of the safety of TNK compared to a contemporaneously treated rt-PA population; and c) confirm the promise of TNK compared to rt PA in reducing poor outcomes following acute ischemic stroke. [unreadable] [unreadable]